The overall goal of this renewal application is to define the mechanism(s) of gene transcription by the vitamin D3 receptor (VDR). To do so, VDR will be described structurally in the context of its actions as both a transcriptional repressor and activator. The role of a newly discovered coactivator complex, called DRIP, that is recruited to nuclear receptors in a ligand-dependent manner and is required by VDR to elicit transcriptional activation at a promoter, will also defined functionally. The overall goals are to apply the information generated here to increase our knowledge of how nuclear receptors regulate gene transcription in response to hormones. The specific aims are: 1) To determine the structure of VDR in transactivating and transrepressing conformations; 2) To generate reagents required for the study of DRIP function in vivo and in vitro; 3) To define the mechanisms of VDR transactivation through coactivators, and 4) To define the mechanism of VDR-mediated coactivation on a complex promoter.